Because tissue stem cells are responsible for renewing and repairing human tissues, drugs that interfere with their function or cause their death are particularly toxic. FIG. 1 illustrates the universal, hierarchal human tissue cell kinetics architecture. Tissue stem cells (NS) subtend tissue turnover units comprised of many dividing and differentiating transient amplifying cells (NT) and terminally differentiated cells (NT-Terminal). As differentiated terminal cells age, expire, and are loss from a given tissue, they are replaced by the division of transient cells, which are in turn replaced by the division of the resident tissue stem cells.
Despite the importance of tissue stem cells in adverse toxic drug effects, currently there are no pre-clinical assays for tissue stem cell toxicity that do not require animals. Even animal testing is indirect, as it involves evaluating the pathological consequences of tissue stem cell toxicity (e.g., tissue dysplasia, anemia). Also, animal models are known to be poor predictors for tissue stem cell toxicity in humans.
A number of factors conspire to cause the current lack of direct pre-clinical assays for tissue stem cell toxicity. Because of their unique place in the universal cell kinetics hierarchy of human tissues, tissue stem cells are a minute fraction of any human tissue cell preparation. As a result, they have proven difficult to isolate in sufficient number or purity to establish reliable assays. For the same reason, no biomarkers for tissue stem cells are available with sufficient specificity to quantify tissue stem cells for drug toxicity testing.
Toxicity against tissue stem cells is one of the most intolerable forms of drug toxicity, which can lead to drug candidate failure late in expensive clinical trials, and potentially after marketing. However, the only currently available pre-clinical tests for detecting human tissue stem cell toxicity are animal models. Such tests are expensive and often do not faithfully predict toxic effects in human patients